Expert Highlights Immunotherapy Combo Strategies in Relapsed/Refractory CRC

A. Craig Lockhart, MD, MHS

The explosion of immunotherapy in oncology has spread to the colorectal cancer (CRC) paradigm, which now has led investigators to evaluate combination approaches with this class of agents and others to elicit greater responses for patients with relapsed/refractory disease, said A. Craig Lockhart, MD, MHS.

Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; FTD/TPI; Lonsurf) are both approved in this setting, explained Lockhart. Although sequencing of these therapies remains a challenge, the potential of combining them with immunotherapy may further benefit patients with microsatellite instability—high (MSI-H) disease. However, as most patients [do] not [have] MSI-H [tumors], strategies are under investigation to spark immune responses in patients with microsatellite-stable (MSS) CRC.

“Everything now is immunotherapy,” said Lockhart. “There are data for chemotherapy agents in combination with immunotherapy affecting the genetics and proteins present on cancer cells. Everyone wants to [find] some combination with one of those agents and immunotherapy.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Lockhart, professor and associate director for Regional and Strategic Clinical Research Affiliations at Sylvester Comprehensive Cancer Center of the University of Miami Health System, discussed ongoing developments and the future of immunotherapy in CRC.

OncLive: What is the state of relapsed/refractory CRC treatment?

Lockhart: We have 2 approved options for the treatment of patients with refractory colon cancer: regorafenib and TAS-102. However, we still need to figure out how to sequence those agents.

There are some data from the REVERCE trial about sequencing EGFR-targeted therapies versus regorafenib. Additionally, the ReDOS study showed an optimal dosing schedule with regorafenib because there are some toxicities with that drug.

We know that about 5% of patients with metastatic CRC have MSI-H tumors. We have well-established data that immunotherapy can be useful for those patients; however, dual immunotherapy in the frontline setting may [be more beneficial].

The biggest problem is that 95% of patients with metastatic CRC have "cold" tumors and therefore, immunotherapy [is not beneficial] for them. We are looking at some strategies to try and make [their tumors "hot"] and potentially responsive to immunotherapy.

Also, the RAS/RAF/MEK/ERK signaling pathway is involved in tumorigenesis in CRC and is a therapeutic pathway that can be targeted. There are different strategies to address resistance that fall within that pathway.

Where can we go next with regorafenib and TAS-102?

There is a fair amount of evidence that TKIs have potential interactions and change the expression of PD-L1 in other cancers. That would be an obvious place to start: [combine either regorafenib or TAS-102] with immunotherapy.

Additionally, bringing those agents further forward [may have some merit]. The REVERCE study looked at cetuximab (Erbitux) given after regorafenib, although most of us haven't been doing that in practice.

In terms of sequencing, [we should] look at different combinations and try to find other spaces where those medications can fit in better. Unfortunately, we are not able to make a lot of those decisions until we identify biomarkers that can help us decide which patients are right for which drug.

How did the ReDOS data have an impact on how you treat patients in clinical practice?

I was somewhat involved with regorafenib during its development process. During the clinical trials, the drug was relatively well tolerated. We didn't have the problems [we are seeing now]. In clinical trials, patients are well selected with good performance status, and there are other factors that make them the ideal patients to treat.

Now that regorafenib [is an option] for the general patient population, we are seeing a lot of toxicities that prevent you from giving the full 160-mg dose for 3 weeks on/1 week off. Quite often, you cannot get patients through that regimen. They have mouth sores, toxicities related to their hands and feet, and elevated liver function test [results].

That being said, if toxicity is limiting your drug delivery, the patients may not get the full benefit of regorafenib. The ReDOS study showed that a dose-escalation schedule of 80 mg, to 120 mg, to 160 mg allowed more patients to get to cycle 3 of treatment.

You mentioned the RAS/RAF/MEK/ERK pathway. What investigational strategies are looking at that pathway?

While probably not true in biology, that pathway looks to be vertical in schematic drawings. We have learned that blocking 1 part of the pathway can lead to escape from another part of the pathway. For example, if you block MEK, you can have escape through ERK.

The [novel] idea is to try to block the pathway at multiple nodes. That has been shown to be somewhat successful in BRAF V600E mutations with cetuximab and vemurafenib (Zelboraf) in animal models. Those data were translated into human studies with the addition of irinotecan.

There are other studies looking at targeting EGFR and MEK simultaneously; however, we need to be cognizant of overlapping toxicities, such as skin rashes and diarrhea. It is a hard pathway to inhibit permanently because of escape, but it is worthwhile to continue targeting multiple nodes of the pathway.

What dual-immunotherapy strategies are being explored?

Recently, data [have shown] that dual-immunotherapy—as it is in melanoma—may be successful in CRC. MSI-H tumors are so rare, so we wanted to see what we could do to inhibit their immune milieu and [elicit a better response].

At the 2018 ESMO Congress, dual inhibition with nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a good overall response rate, progression-free survival, and manageable toxicity. It was a relatively small study, but it is something that could be considered in the frontline setting.

Physicians who have experience [treating patients with] melanoma or renal cell carcinoma are comfortable with this combination, and it makes sense scientifically. It might be a winner at this point.

What is your hope for patients with MSS tumors going forward?

The group at the Sarah Cannon Research Institute had a study of cobimetinib (Cotellic) plus a PD-L1 inhibitor. The idea was to make a "cold" tumor "hot" and turn on the immune response.

Unfortunately, the study was negative, but I do like that as a strategy. Immunotherapy is the single-most important therapeutic [approach] that has come along in oncology. Trying to make those drug work for more patients across the board is a good [goal].